Effects of steady-state female hormones on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide

Background/Rationale: Roflumilast (ROF) is an oral, selective phosphodiesterase 4 (PDE4) inhibitor licensed for the treatment of severe COPD. It is mainly metabolised by cytochrome P450 (CYP) 1A2 and 3A4 to roflumilast N-oxide (RNO), which mediates >90% of ROF total PDE4 inhibitory activity (tPDE4i), and is then mainly cleared by CYP3A4. Female hormones such as ethinyloestradiol and gestodene can inhibit the metabolism of CYP1A2 and 3A4 substrates; the pharmacokinetic (PK) effects, safety and tolerability of their coadministration with ROF were therefore investigated. Methods: In a phase I, open-label, two-period PK study, 20 women received a single dose of ROF 500μg with/without concomitant oral administration of a daily fixed dosing to steady state of gestodene 0.075mg plus ethinyloestradiol 0.03mg. Blood samples were taken for the analysis of ROF and RNO over 120 hours after ROF dosing. Results: After coadministration, total systemic exposure for ROF (AUCinf) increased to 151% (90% CI 122, 187%) of reference, and peak concentration (Cmax) increased to 138% (90% CI 121, 158%). For RNO, the AUCinf was 114% (90% CI 96.6, 134%) after coadministration, while Cmax decreased to 87.6% (90% CI 80.4, 95.5%). The tPDE4i rose to 117% (90% CI 98.8, 138%). The combination of ROF and female hormones was well tolerated and there were no safety concerns. Conclusions: No clinically relevant interaction between ROF/RNO and gestodene plus ethinyloestradiol was observed. These results suggest that ROF may be used without dose adjustments with other exogenous female hormones, including those used in hormone replacement therapy.